Novel anti-diarrheal 4-azatricyclo[4.3.1.13,8 ] undecane derivatives

ABSTRACT

The present invention, comprehends a method for treating diarrhea comprising administering to an animal in need of anti-diarrheal treatment an effective anti-diarrheal amount of a compound of the formula ##STR1## and acid addition salts thereof wherein Y is alkylene containing 1-4 carbon atoms; R 2  and R 3  together with N is a heterocyclic ring system comprising azamonocyclic ring of the formula ##STR2## wherein Z is phenylhydroxymethylmethylene, phenylhydroxymethylene, phenylcarboxymethylene, phenylcarbalkoxymethylene or azabicycloalkyl or phenyl or hydroxyl substituted azabicycloalkyl containing 6-9 carbon atoms and containing at least 5 atoms in each ring of the azabicycloalkyl or 4-azatricyclo[4.3.1.1 3 ,8 ]undec-4-yl; Ar 1  and Ar 2  are phenyl, halo-substituted phenyl, (lower alkyl) substituted phenyl, pyridyl, thienyl or furyl, and Ar 3  is phenyl, halo-substituted phenyl, (lower alkyl) substituted phenyl, pyridyl, thienyl, furyl, pyrrolyl, imidazoyl, oxazolinyl, oxazolinyl, thiazolinyl, thiazolyl, 1,2,4-oxodiazolyl, and isoxazolinyl. The present invention also comprehends novel compounds included in the above formula.

This is a division of Ser. No. 733,503 filed Oct. 18, 1976, now U.S.Pat. No. 4,057,549, which is in turn a division of Ser. No. 568,439,filed Apr. 16, 1975, now U.S. Pat. No. 3,998,832.

The present invention encompasses a method for treating diarrheacomprising administering to an animal in need of antidiarrheal treatmentan effective antidiarrheal amount (0.1 to 25 mpk) of a compound of theformula ##STR3## and the pharmaceutically acceptable acid addition saltsthereof wherein Y is alkylene containing 1-4 carbon atoms; R₂ and R₃together with N is a heterocyclic ring system comprising azamonocyclicring of the formula ##STR4## wherein Z is hydroxymethylmethylene,phenylhydroxymethylmethylene, phenylhydroxymethylene,phenylcarboxymethylene, phenylcarbalkoxymethylene or an azabicycloalkylor phenyl or hydroxyl substituted azabicycloalkyl containing 6-9 carbonatoms and containing at least 5 atoms in each ring of theazabicycloalkyl or 4-azatricyclo[4.3.1.1³,8 ]undec-4-yl; Ar₁ and Ar₂ arephenyl, halo-substituted phenyl, (lower alkyl) substituted phenyl,pyridyl, thienyl or furyl, and Ar₃ is phenyl, halo-substituted phenyl,(lower alkyl) substituted phenyl, pyridyl, thienyl, furyl, pyrrolyl,imidazoyl, oxozolyl, oxazolinyl, thiazolinyl, thiazolyl,1,2,4-oxodiazolyl, and isoxazolinyl.

Embodiments of the present invention involving administration ofcompounds of the formula ##STR5## or acid addition salts thereof whereinR₂ and R₃ together with N is an azabicycloalkyl containing 6-9 carbonatoms and containing at least 5 atoms in each ring of theazabicycloalkane; Ar₁ and Ar₂ are phenyl, halo-substituted phenyl,(lower alkyl) substituted phenyl, pyridyl, thienyl, or furyl, and Ar₃ isphenyl, halo-substituted phenyl, (lower alkyl) substituted phenyl,pyridyl, thienyl, furyl, Y is alkylene containing 1-4 carbon atoms areillustrated by the administration to an animal in need of anti-diarrhealtreatment an effective antidiarrheal amount of2-(3,3,3-triphenylpropyl)-2-azabicyclo[2.2.2]octane,2-3,3-diphenyl-3-(2-pyridyl)propyl]-2-azabicyclo[2.2.2]octane,2-[3,3diphenyl-3-(3-pyridyl)propyl]-2-azabicyclo[2.2.2]-octane,2-[3,3,diphenyl-3-(2-furyl)propyl]-2-azabicyclo-[2.2.2]octane, or2-[3,3-diphenyl-3-(2-thienyl)propyl]-2-azabicyclo[2.2.2]octane.

An embodiment of the present invention comprises a method of treatingdiarrhea comprising administering to an animal in need of anti-diarrhealtreatment an effective antidiarrheal amount (0.1 to 25 mpk) of acompound of the formula ##STR6## and pharmaceutically acceptable acidaddition salts thereof wherein Y is alkylene containing 1-4 carbonatoms; R₂ and R₃ together with N is heterocyclic ring system comprisingazamonocyclic ring of the formula ##STR7## wherein Z ishydroxymethylmethylene phenylhydroxymethylene, phenylcarboxymethylene,phenylcarbalkoxymethylene or an azabicycloalkyl or phenyl or hydroxylsubstituted azabicycloalkyl containing 6 to 9 carbon atoms andcontaining at least 5 atoms in each ring of the azabicycloalkyl or4-azatricyclo[4.3.1.1³,8 ]undec-4-yl; Ar₁, Ar₂ and Ar₃ are phenyl,halo-substituted phenyl, (lower alkyl) substituted phenyl, pyridyl,thienyl or furyl.

The present invention encompasses a compound of the formula ##STR8## andthe pharmaceutically acceptable acid addition salts thereof wherein Y isalkylene containing 1-4 carbon atoms; R₂ and R₃ together with N is aheterocyclic ring system comprising azamonocyclic ring of the formula##STR9## wherein Z is hydroxymethylmethylene,phenylhydroxymethylmethylene, phenylhydroxymethylene,phenylcarboxymethylene, phenylcarbalkoxymethylene or azabicycloalkyl orphenyl or hydroxyl substituted azabicycloalkyl containing 6 to 9 carbonatoms and containing at least 5 atoms in each ring of theazabicycloalkyl or 4-azatricyclo[4.3.1.1³,8 ]undec-4-yl; Ar₁ and Ar₂ arephenyl, halo-substituted phenyl, (lower alkyl) substituted phenyl,pyridyl, thienyl or furyl, and Ar₃ is phenyl, halo-substituted phenyl,(lower alkyl) substituted phenyl, pyridyl, thienyl, furyl, pyrrolyl,imidazoyl, oxazolyl, oxazolinyl, thiazolinyl, thiazolyl,1,2,4-oxodiazolyl, and isoxazolinyl. The term halo includes fluor,chloro, bromo, and iodo. The term lower alkyl includes alkyl radicalshaving 1-7 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl,pentyl, hexyl, and heptyl. The term alkylene containing 1-4 carbon atomsincludes such alkylene radicals as methylene, ethylene, propylene,isopropylene, and butylene.

Compounds in which R₂ and R₃ together with N is an azabicycloalkane orphenyl or hydroxyl substituted azabicycloalkane containing 6-9 carbonatoms and containing at least 5 atoms in each ring and wherein Ar₁, Ar₂,and Ar₃ as defined in the preceeding paragraph are particularly usefulin practicing the present invention in that they are potentantidiarrheal agent with minor, if any, central nervous system effecti.e., there is unexpectedly a distinct separation of central nervoussystem and antidiarrheal properties. These compounds are antidiarrhealcompounds without central nervous system effecting properties. Compoundsof the formula ##STR10## and acid addition salts thereof wherein Ar₁ andAr₂ are phenyl, halo-substituted phenyl, (lower alkyl) substitutedphenyl, pyridyl, thienyl, or furyl, and Ar₃ is phenyl, halo-substitutedphenyl, (lower alkyl) substituted phenyl, pyridyl, thienyl, furyl,pyrrolyl, imidazoyl, oxazolinyl isoxazolinyl, thiazolinyl, thiazolyl,1,2,4-oxadiazolyl or isoxazolinyl are particularly preferred. Otherpreferred azabicyclo radicals such as 3-azabicyclo[3.2.2]non-3-yl,6-azabicyclo[3.2.1]oct-6-yl, 7-azabicyclo[2.2.1]hept-7-yl,8-azabicyclo[4.3.0]non-8-yl, 2-azabicyclo[3.3.1]non-2-yl,5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl,5-hyroxy-5-phenyl-2-azabicyclo[2.2.2]oct-2-yl,4-phenyl-2-azabicyclo[2.2.2]-oct-2-yl, 2-aza-5,6,1;2-(benzo)bicyclo[2.2.2]oct-2-yl, 6-hydroxy-2-azabicyclo-[2.2.2]oct-2-yl,and 2-aza-4-phenyl-5,6,1',2'(benzo)bicyclo[2.2.2]oct-2-yl and2-azabicyclo[2.2.1]hept-2-yl may replace the 2-azabicyclo[2.2.2]oct-2-ylradical.

Compounds of the formula ##STR11## and the pharmaceutically acceptableacid addition salts thereof wherein R₂ and R₃ together with N is anazabicycloalkyl or phenyl or hydroxyl substituted azabicycloalkyl having6-9 carbon atoms and having at least 5 atoms in each ring; Ar₁ and Ar₂are phenyl, halo-substituted phenyl, (lower alkyl) substituted phenyl,pyridyl, thienyl or furyl; and Ar₃ is phenyl, halo-substituted phenyl,(lower alkyl) substituted phenyl, pyridyl, thienyl, furyl are preferred.

Compounds of the formula ##STR12## and the pharmaceutically acceptableacid addition salts thereof wherein Ar₁ and Ar₂ are phenyl,halo-substituted phenyl, (lower alkyl) substituted phenyl, pyridyl,thienyl or furyl, and Ar₃ is phenyl, halo-substituted phenyl, (loweralkyl) substituted phenyl pyridyl, thienyl, or furyl are furtherpreferred.

Compounds of the formula ##STR13## and the acid addition salts thereofwherein Ar₃ is phenyl, halo-substituted phenyl, (lower alkyl)substituted phenyl, pyridyl, thienyl, furyl, pyrrolyl, imidazoyl,oxazolyl, oxazolinyl, thiazolinyl, thiazolyl, 1,2,4-oxadiazolyl, orisoxazolinyl are preferred.

Compounds of the above formula wherein Ar₃ is phenyl or pyridyl areespecially preferred by virtue of separation of anti-diarrheal andcentral nervous system affecting properties.

Compounds of the formula ##STR14## and the pharmaceutically acceptableacid addition salts wherein Ar₃ is phenyl or pyridyl are likewise usefulanti-diarrheal agents. These compounds are exemplified by4-[3,3-(diphenyl)-3-(-3-pyridyl)propyl]-4-azatricyclo[4.3.1.1³,8]undecane and 4-(3,3,3-triphenylpropyl)-4-azatricyclo[4.3.1.1³,8]undecane.

Compounds of the formula ##STR15## and the pharmaceutically acceptableacid addition salts thereof wherein Ar₁ and Ar₂ are phenyl,halosubstituted phenyl, (lower alkyl) substituted phenyl, or pyridyl arealso preferred. For example2-[3,3-diphenyl-3-(2-thienyl)propyl]-2-azabicyclo[2.2.2]octane ispreferred.

Compounds of the formula ##STR16## and the acid addition salts thereofwherein Ar₁ and Ar₂ are defined as before are preferred. For example2-[3,3-diphenyl-3-(2-furyl)propyl]-2-azabicyclo[2.2.2]═octane ispreferred.

Compounds of the formula ##STR17## and the acid addition salts thereofwherein Ar₁ and Ar₂ are as defined earlier are also preferred.

Compounds of the formula ##STR18## and the acid addition salts thereofwherein Ar₁ and Ar₂ are as defined earlier are also preferred.

Compounds of the formula ##STR19## and the acid addition salts thereofwherein Ar₁ and Ar₂ are as defined earlier are also preferred.

Compounds of the formula ##STR20## and the acid addition salts thereofwherein Ar₁ and Ar₂ are as defined earlier are also preferred.

Compounds of the formula ##STR21## and the acid addition salts thereofwherein Ar₁ and Ar₂ are as defined earlier are also preferred.

Compounds of the present invention are prepared by the method set out inScheme I ##STR22## wherein Ar₁, Ar₂, Ar₃, R₁ and R₂ are as previouslydescribed.

SCHEME I

Esters described in U.S. Pat. No. 3,839,576 are suitable intermediatesfor compounds useful in practicing the present invention. Thus compoundsof the formula ##STR23## wherein R is phenyl or thienyl may behydrolysed to the corresponding acid by alcoholic potassium hydroxideand the resulting acid may be converted to the corresponding acidchloride which, in turn, is converted to the compounds of the presentinvention as set out in Scheme I.

Scheme I represents a combination of methods described by S. Patai andS. Dayagi J. C. S. 716 (1962) and D. Martensson and E. Nilsson ActaChem. Scand. 19 (3) 711 (1965), CA-63-6968h.

Alternately compounds prepared in Scheme I may be produced by thefollowing reaction ##STR24##

The organic bases of this invention form non-toxic, acid-addition saltswith a variety of organic and inorganic acids. Such salts are formedwith acids such as sulfuric, phosphoric, hydrochloric, hydrobromic,hydriodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric,cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.

The starting alcohol shown in Scheme I is prepared as shown in SchemeII. ##STR25##

SCHEME II

Thus 1 part of triphenylcarbinol is reacted with 2 parts of malonic acidat 170° for 3 hours to provide 3,3,3-triphenylpropionic acid and thisacid is converted into the acid chloride by reaction with thionylchloride. Reacting the acid chloride with 2 parts of2-azabicyclo[2.2.2]octane provides the amide,2-(3,3,3-triphenylpropionyl)-2-azabicyclo[2.2.2]octane and reduction ofthis amide with 1 part of LiAlH₄ in tetrahydrofuran provides2-(3,3,3-triphenylpropyl)-2-azabicyclo[2.2.2]octane. The addition ofconcentrated hydrochloric acid to an ethereal solution of above amineprovides 2-(3,3,3-triphenyl propyl)-2-azabicyclo[2.2.2]octanehydrochloride, melting at 221°-223° C.

Alternately compounds of the present invention may be prepared as setout in Scheme III ##STR26##

SCHEME III

This method represents a modification of methods described by Martenssonand Nilson, Acta Chem. Scand. 19 )3), 711-12 (1965) - CA-63-6968h. Thus,1 part of 2-(2-phenylbenzyl) pyridine is reacted with 1 part of n-Butyllithium in tetrahydrofuran at -70° C. and then reacted with 1 part of2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane to provide2-[3,3-diphenyl-3-(2-pyridyl)propyl]-2-azabicyclo[2.2.2]octane.

Ring closure methods are also useful for preparing compounds of thepresent invention as set out in Scheme IV. ##STR27## wherein Y, R₂, R₃,Ar₁ and Ar₂ are as defined before and R₄ and R₅ are lower alkylcontaining 1-7 carbon atoms or hydrogen. ##STR28## wherein Y, R₂, R₃,Ar₁ and Ar₂ are as defined before and R₆ is lower alkyl containing 1-7carbon atoms. ##STR29## wherein Y, R₂, R₃, Ar₁ and Ar₂ are as definedbefore. ##STR30## wherein Y, R₂, R₃, Ar₁ and Ar₂ are as previouslydescribed and R₈ is lower alkyl containing 1-7 carbon atoms.

Anti-diarrheal utility of the instant compounds is evidenced by theirability to inhibit gastrointestinal propulsion as set out in thefollowing test.

CHARCOAL MEAL TEST

Mice weighing 18-24 grams and previously fasted for 24 hours are eachgiven orally 0.2 ml. of a suspension containing 10% charcoal and 1%methylcellulose. The test compounds are administered intragastricallyone hour prior to the charcoal meal. 3.5 Hours after administration ofthe meal the mice are sacrificed by cervicle dislocation and the cecumis examined for the presence of absence of charcoal on an all or nonebasis. Each compound is tested at three dose levels (typically 30, 10, 3mg/kg) in groups of 6 mice per dose level. Control groups of mice givensaline only were run concurrently with each test group.

CASTOR OIL-INDUCED DIARRHEA TEST

Following the experimental design of Niemegear et al. Arzniem - Forsch22: 515-518 (1972). Adult male Charles River rats weighing 180-200 gramsin groups of 12 are fasted in community cages for 24 hours prior to thetest with free access to water. The test compounds were in 0.5% methylcellulose suspension at 2.0 ml/kg. The control constitutes the vehicleonly. One hour after the compound administration, 1.0 m. of castor-oilwas given to each rat intragastrically. The rats were then observed forthe presence or absence of diarrhea at hourly intervals for up to 8hours, post administration of castor-oil. The median effective dosevalue (ED50) was calculated using the method of Berkson, J. Amer.Statist, Assoc. 48 565-99 (1953). Lack of central nervous systemeffective properties are shown by the following test.

MOUSE HOT PLATE TEST

A mouse (adult male weighing 18-25 grams) is placed in a restrainingcylinder on a hot plate with the temperature controlled at 55 ± 0.3° C.The reaction time of the mouse to lick a foot or jump is measured at 60,40 and 20 minutes before and 30, 60, 90, and 120 minutes afteradministration of the test compound. The "normal" reaction time ismeasured as the median of the three pretreatment reaction times. Apositive response consists of a reaction time greater than twice thenormal time at any of the post treatment times. A dose (50 mg/kgadministered intraperitoneally) of the test compound is consideredactive when 50 percent or more of the animals used show a positiveresponse.

TAIL CLIP TEST

A special clip is applied to the base of the tail of the mouse (adultmale weighing 18-25 grams) and the time for the animal to turn around tobit at it is measured. The sensitivity of each mouse is determinedone-half hour prior to drug administration. Only those mice attemptingto bite the clip are included in the experiment. The test compound isthen administered intraperitoneally and the response to placement of theclip is determined at 30, 60, 90, and 120 minutes after treatment. Aresponse is considered positive if the animal takes more than 2 timesthe pre-drug time to bite at the clip at any of these time intervals. Atest compound is considered active when 50 percent or more of theanimals used show a positive response.

The compounds herein described can be combined with pharmaceuticallyacceptable carriers to provide novel pharmaceutical compositons. Theconcentration of active ingredient in the composition is not critical,but is preferably 1-80%. These compositions ca be administered orally,suitable forms for such administration including tablets, lozenges,capsules, dragees, pills, powders, solutions, suspensions and syrups.Acceptable pharmaceutical carriers are exemplified by gelatin capsules;sugars such as lactose or sucrose; starches such as corn starch orpotato starch; cellulose derivatives such as sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, or cellulose acetatephthalate; gelatin; talc; calcium phosphates such as dicalcium phosphateor tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; acacia; polyvinyl alcohol; stearic acid; alkaline earthmetal stearates such as magnesium stearate; oils such as peanut oil,cottonseed oil, sesame oil; olive oil, corn oil, oil of theobroma;water; agar; alginic acid; and benzyl alcohol, as well as othernon-toxic compatible substances used in pharmaceutical formulations.

The compounds of this invention can be used to produce an antidiarrhealeffect in mammals by administering the instant novel compositionscontaining a therapeutically effective amount of the active ingredient.The term "therapeutically effective amount" is defined as the amount ofactive ingredient that will produce an antidiarrheal effect, i.e., whichwill reverse, inhibit or prevent diarrhea. For a particular subject, theamount of active ingredient to be used will vary with the subjectinvolved, the severity of the diarrhea, and the particular activeingredient used. The therapeutically effective amount of a particularactive ingredient can be determined by comparing its potency to that ofa known standard, for which the therapeutic dosage is known. Typically0.1-25 mg./kg. is an effective antidiarrheal amount of a given compound.

Those skilled in the art will recognize that observations of activity instandardized tests for particular biological effects are fundamental tothe development of valuable new drugs, both veterinary and human.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirpreparation. It will be apparent to those skilled in the art that manymodifications, both of materials and of methods, may be practicedwithout departing from the purpose and intent of this disclosure.Throughout the examples hereinafter set forth, temperatures are given indegrees centigrade (° C.).

EXAMPLE 1

A mixture of 2 parts of triphenyl carbinol and 8 parts of malonic acidare heated at 170° for 3 hours. This mixture is cooled and dissolved inhot ethanol. 3,3,3-Triphenylpropionic acid, melting at 182°,crystallizes from the ethanol upon cooling. 1 Part of3,3,3-triphenylpropionic acid is refluxed with 5 parts of thionylchloride for 4 hours and the excess thionyl chloride is removed invacuum to provide the crude 3,3,3-triphenyl propionyl chloride. 1 Partof this acid chloride is reacted with 2 parts of2-azabicyclo[2.2.2]octane in 50 parts of benzene. The precipitated amideis filtered and the benzene solution washed with water, dried withmagnesium sulfate, and the benzene evaporated. The remaining oil iscrystallized to provide2-(3,3,3-triphenylpropionyl)-2-azabicyclo[2.2.2]octane. 0.9 Parts ofthis material is reacted with 0.37 parts of lithium aluminum hydride in15 parts of tetrahydrofuran at reflux for 5 hours. The reaction mixtureis cooled and treated with 15% aqueous sodium hydroxide solution todecompose any unreacted lithium aluminum hydride. The reaction mixtureis filtered and the solvent is removed in vacuo to provide a residualoil which is taken up in ether. The ether soln. is extracted c 10% HClforming an insoluble gum, which is dissolved in methylene chloride,dried over anhydrous sodium sulfate and evaporated providing2-(3,3,3-triphenylpropyl)-2-azabicyclo[2.2.2]octane hydrochloride,melting at 222°-223° C. This compound has the following molecularformula. ##STR31##

This compound has an ED50 = 6.3 ± 3.0 mkp via intragastricadministration to mice in the charcoal meal test.

EXAMPLE 2

Following the procedures set out in Example 1, 1 part of3,3,3-triphenylpropionyl chloride and 2 parts of4-hydroxy-4-phenylpiperidine are reacted to provide1-(3,3,3-triphenylpropionyl)-4-hydroxy-4-phenylpiperidine. 0.23 Parts ofthis amide is reacted with 0.05 parts of lithium aluminum hydride in 3.0parts by volume of ethyl ether to provide1-(3,3,3-triphenylpropyl)-4-hydroxy-4-phenylpiperidine. This compoundhas the following structural formula ##STR32## Administration of thismaterial inhibits diarrhea in animals in need of antidiarrhealtreatment.

EXAMPLE 3

Following the procedures set out in Example 1, 1 part of3,3,3-triphenylpropionyl chloride and 2 parts of hexahydroazepine arereacted to provide 1═(3,3,3-thiphenylpropionyl)hexahydroazepine. 0.4Part of this amide is reacted with 0.05 part of lithium aluminum hydridein 3.0 parts by volume of ethyl ether to provide1-(3,3,3-triphenylpropyl)hexahydroazepine. This compound has thefollowing structural formula. ##STR33##1-(3,3,3-triphenylpropyl)hexahydroazepine hydrochloride melting at208°-211° is prepared by treating the free base with hydrochloric acid.

EXAMPLE 4

1 Part of 3,3-(diphenyl)-3-(2-thienyl)propionyl chloride (Martenson andNilson Acta Chem. Scand. 19 711, (1965) is reacted with 20 parts of2-azabicyclo[2.2.2]octane in 50 parts of benzene. The precipitated amideis filtered and the benzene solution washed with water, dried withmagnesium sulfate, and the benzene evaporated. The remaining oil iscrystallized to provide2-[3,3-diphenyl-3-(2-thienyl)propionyl]2-azabicyclo[2.2.2]octane. Thisamide is reduced with lithium aluminum hydride as described in Example 1to provide2-[3,3-diphenyl-3-(2-thienyl)propyl]2-azabicyclo[2.2.2]octane. Thiscompound has the following structural formula ##STR34##

EXAMPLE 5

Reaction of 2.5 parts of diphenyl-2-pyridylmethane in 60 parts by volumeof cyclohexane with an equivalent of butyl lithium at 10° C. undernitrogen is followed by the addition of 2.1 parts2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane in cyclohexane provide afterquenching and isolation2-[3,3-diphenyl-3-(2-pyridyl)propyl]-2-azabicyclo[2.2.2]octane as anoil. Reaction of this amine with oxalic acid in methanol provides theoxalic acid salt, melting at 191.5°-192.5°, having the followingformula. ##STR35##

EXAMPLE 6

Following the procedure in Example 5 and substituting 0.39 parts of sodaamide for butyl lithium and 2.5 parts of diphenyl-4-pyridylmethane forthe 2-pyridyl isomer provides2-[3,3-diphenyl-3-(4-pyridyl)propyl]-2-azabicyclo[2.2.2]octane, meltingat 112°-114° C. This compound has the following formula. ##STR36##

EXAMPLE 7

Following the procedure in Example 1, 2 parts ofdi-4-methoxyphenyl-4-methylphenylcarbinol is converted to2-[3,3-(4-methoxyphenyl)-3-(4-methylphenyl)propyl]-2-azabicyclo[2.2.2]octane.This compound has the following structural formula. ##STR37##

EXAMPLE 8

Following the procedure in Example 1, 2 parts ofdi-4-chlorophenyl-4-ethoxyphenylcarbinol is converted to2-[3,3-(4-chlorophenyl)-3-(4-ethoxyphenyl)propyl]-2-azabicicyclo[2.2.2]octane.This compound has the following structural formula. ##STR38##

EXAMPLE 9

Following the procedure in Example 1, 2 parts ofdiphenyl-2-(4-methyl-2-furyl)carbinol is converted to2-[3,3-diphenyl,-3(5-methyl-2-furyl)propyl]-2-azabicyclo[2.2.2]octane.This compound has the following structural formula. ##STR39##

EXAMPLE 10

Following the procedure in Example 1, 2 parts ofdi-(4-fluorophenyl)-4-ethylcarbinol and using 6-azabicyclo[3.sup..2.sup.. 1]octane as the amine is converted to6-[3,3-(4-fluorophenyl)-3-(4-ethylphenyl)propyl]-6-azabicyclo[3.2.1]octanehaving the following structural formula. ##STR40##

EXAMPLE 11

Following the procedures set out in Example 1, 27.0 parts ofnorpethidine is reacted with 9 parts of triphenylpropionic acid chloridein the presence of 4 parts of triethylamine in benzene solvent. Theresulting amide is reduced with 5 parts of lithium aluminum hydride toprovide 1-(3,3,3-triphenylpropyl)-4-hydroxymethyl-4-phenylpiperidine.##STR41## Administration of this material inhibits diarrhea in animalsin need of antidiarrheal treatment.

EXAMPLE 12

Following the procedures set out in Example 1, 1 part of3,3,3-triphenylpropionyl chloride and 2 parts of5-hydroxy-2-azabicyclo[2.2.2]octane are reacted to provide2-(3,3,3-triphenylpropionyl)-5-hydroxy-2-azabicyclo[2.2.2]octane. 0.23Parts of this material is reacted with 0.05 parts of lithium aluminumhydride in 3.0 parts by volume of ethyl ether to provide2-(3,3,3-triphenylpropyl)-5-hydroxy-2-azabicyclo[2.sup.. 2.sup..2]octane. This compound, isolated as the hydrochloride salt, has thefollowing structural formula. ##STR42## Administration of this materialinhibits diarrhea in animals in need of antidiarrheal treatment.

EXAMPLE 13

Following the procedures set out in Example 1, 1 part of3,3,3-triphenylpropionyl chloride and 2 parts of2-azabicyclo[3.3.1]nonane are reacted to provide2-(3,3,3-triphenylpropionyl)-2-azabicyclo[3.sup.. 3.sup.. 1]nonane. 0.23Parts of this amide is reacted with 0.05 parts of lithium aluminumhydride in 3.0 parts by volume of ethyl ether to provide2-(3,3,3-triphenylpropyl)-2-azabicyclo[3.3.1]nonane. This compound,isolated as the hydrochloride, has the following structural formula.##STR43## Administration of this material inhibits diarrhea in animalsin need of antidiarrheal treatment.

EXAMPLE 14

Following the procedures set out in Example 1, 1 part of3,3,3-triphenylpropionyl chloride and 2 parts of4-phenyl-2-azabicyclo[2.2.2]octane are reacted to provide2-(3,3,3-triphenylpropionyl)-4-phenyl-2-azabicyclo[2.2.2]octane. 0.23Parts of this material is reacted with 0.05 parts of lithium aluminumhydride in 3.0 parts by volume of ethyl ether to provide2-(3,3,3-triphenylpropyl)-4-phenyl-2-azabicyclo[2.2.2]octane. Thiscompound isolated as the hydrochloride, has the following structuralformula. ##STR44## Administration of this material inhibits diarrhea inanimals in need of antidiarrheal treatment.

EXAMPLE 15

Following the procedures set out in Example 1, 3.0 parts of3,3,3-triphenylpropionyl chloride and 2.0 parts ofacenaphto[1,2-C]pyrrolidene are reacted to provide8-(3,3,3-triphenylpropionyl)acenaphto[1,2-C]pyrrolidine, melting at159°-168°. 3.5 Parts of this amide are reacted with 3.6 parts of lithiumaluminum hydride in tetrahydrofuran to provide8-(3,3,3-triphenylpropyl)acenaphtho[1,2-C]pyrrolidine. This compound hasthe following structural formula. ##STR45##

EXAMPLE 16

Following the procedures set out in Example 1, 3.0 parts of3,3,3-triphenylpropionyl chloride and 2.0 parts ofbenzo[C]tetrahydropyridine are reacted to provide2-(3,3,3-triphenylpropinyl)benzo[C]tetrahydropyridine hydrochloride. 4.6Parts of this amide and 3.0 parts of lithium aluminum hydride intetrahydrofuran to provide2-(3,3,3-triphenylpropyl)benzo[C]tetrahydropyridine hydrochloride,melting at 216°-223°. This compound has the following structuralformula. ##STR46##

EXAMPLE 17

Following the procedure set out in Example 1, 3.0 parts of3,3,3-triphenylpropionyl chloride and 2.0 parts of ethyl isonipecotateare reacted to provide 2-(3,3,3-triphenylpropionyl)-4-ethoxycarbonylpiperidine. Reduction of 5.0 parts of this material with 3.0 parts oflithium aluminum hydride in tetrahydrofuran provides1-(3,3,3-triphenylpropyl)-4-hydroxymethylpiperidine, melting at142.5°-144°. This compound has the following structural formula.##STR47##

EXAMPLE 18

Following the procedure set out in Example 5, and substituting 0.39parts of soda amide for butyl lithium and 2.5 parts ofdiphenyl-3-pyridyl methane for the 2-pyridyl isomer provides2-[3,3-diphenyl-3-(3-pyridyl)propyl]azabicyclo[222]octane. This compoundhas the following structural formula. ##STR48##

EXAMPLE 19

To 3.5 parts of4-(2-azabicyclo-2.2.2-octane-2-yl(2,2-diphenylbutyraldehyde oxime --prepared from the corresponding nitrile by reduction with diisobutylaluminim hydride, followed by hydrolysis, and reaction with hydroxylamine to provide the oxime -- in 100 parts of dry benzene is added 2parts of phosphoryl chloride and the mixture is refluxed for 30 minutes.The solvent is removed under pressure and the resiude taken up in 50parts of dry toluene, cooled to 0° C, and a cold solution of 1 part oftriethylamine and 5 parts of 2-butyne in 10 parts of toluene. Themixture is stirred at 0° for 3 hours, washed with water, and thesolvents evaportated. The residue is crystallized from ether-hexane toprovide3-[1,1-dipehnyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]4,5-dimethylisoxazole.This compound has the following structural formula. ##STR49##

EXAMPLE 20

To 3.6 parts of4-(2-azabicyclo-2.2.2-oct-2-yl)-2,2-diphenylbutyramidoxime (prepared bythe reaction of the corresponding nitrile with hydroxylamine inmethanol/ sodium methoxide) in 20 parts of dry pyridine is added 5 partsof acetic anhydride. The mixture is heated by steam for 1 hour and thesolvent is evaporated at reduced pressure. The residue is stirred indilute sodium bicarbonate solution and extracted into methylenechloride. The methylene chloride is separated and removed by evaporationat reduced pressue. The product is heated at 150° C for 1 hour, cooledand the product is crystallized from ethanol to provide3-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-5-methyl-1,2,4-oxadiazole,having the following structural formula ##STR50##

EXAMPLE 21

β-Thienyl-β-phenyl-β-imidazolyl propionic acid ethyl ester described inU.S. Pat. No 3,839,576 is with base and converted to the acid chloridewith thionyl chloride and 2 parts of the acid chloride is reacted with 2parts of 2-azabicyclo[2.2.2]octane in acetonitrile to provide thecorresponding amide. 0.9 Parts of the amide is reduced with 0.37 partsof lithium aluminum hydride in 15 parts of tetrahydrofuran by methodsset out in Example 1. The product obtained upon isolation is2-[3-imidazolyl-3-phenyl-3-(2-thienyl)propyl]-2-azabicyclo-[2.2.2]octane.This compound has the following structural formula. ##STR51##

EXAMPLE 22

Reaction of 2.5 parts of diphenyl-3-pyridylmethane in 60 parts by volumeof cyclohexane with an equivalent amount of butyl lithium at 10° C undernitrogen is followed by the addition of 2.1 parts of4-(2-chloroethyl)-4-azatricyclo[4.3.1.1³,8 ]undecane [preparable bymixing the hydrochloride thereof (U.S. Pat. No. 3,845,038) with excessaqueous sodium carbonate, extracting the mixture with toluene, andconsecutively washing the extract with water, drying it over anhydroussodium sulfate, filtering out the drying agent, and removing the solventby vacuum distillation]. Quenching of the reaction with water andisolation by extraction with ether, washing, drying and evaporation ofsolvent provides4-[3,3-(diphenyl)-3-(3-pyridyl)propyl[-4-azatricyclo[4.3.1.1³,8]undecane having the following structural formula ##STR52##

Originating this sequence of reaction with triphenylmethane and usingequivalent quantities provides4-(3,3,3-triphenylpropyl)-4-azatricyclo[4.3.1.1³,8 ]undecane.

EXAMPLE 23

Following the procedures set out in Example 1, 9 parts of3,3-diphenyl-3-(3-pyridyl)propionyl chloride and 27 parts ofnorpethidine are reacted in the presence of 4 parts of triethylamine inbenzene solvent. The resulting amide is reduced with 5 parts of lithiumaluminum hydride to provide1-[3,3-diphenyl-3-(3-pyridyl)propyl]-4-hydroxymethyl-4-phenylpiperidinehaving the following structure.

What is claimed is:
 1. A compound of the formulaand the pharmaceuticallyacceptable acid addition salts thereof wherein Ar₃ is phenyl or pyridyl.